Project Summary/Abstract Schizophrenia (SZ), one of the most disabling mental illnesses, is also associated with increased medical comorbidity and a 20-year shorter life-span than the general population, which together suggest that SZ is characterized by accelerated aging. To examine that hypothesis, this application for a 5-year renewal of our R01 in SZ represents a unique opportunity to evaluate 10-year trajectories of aging in persons with SZ and healthy comparison subjects (HCs), and to expand the focus to examine serious real world consequences (physical comorbidity and mortality), potentially modifiable risk factors, and inflammatory and cellular markers of aging. Per our original proposal, employing a Multi-Cohort Longitudinal Design (MCLD), we have developed a sex- and age-stratified cohort of 140 subjects with SZ and 120 HCs, aged 26-65 years at baseline. These participants are evaluated clinically every year, and with a panel of selected markers representative of biological aging in alternate years. The biomarkers include systemic measures of inflammatory processes (high-sensitivity C-reactive protein or hs-CRP, along with another cytokine and two chemokines), metabolic dysregulation (Homeostatic Model Assessment of Insulin Resistance; HOMA-IR), oxidative stress (F2- isoprostanes), and cellular aging (telomere length). We are currently in the 49th month of the 5-year project, but are proposing this competitive renewal prior to its completion, to avoid a gap in funding and ensure retention of this invaluable, well-characterized existing cohort. Our retention rate has been excellent (95% annually for SZ). We have preliminary evidence consistent with accelerated biological aging in SZ; however, a 10-year expanded study with additional novel aims and innovative measures is necessary to characterize consequences and risk factors of acceleration, and examine the mechanistic role of gene expression and signaling pathways related to inflammation. The proposed renewal has been designed and informed by our initial findings, and by the evolving literature on inflammation and other biological and cellular mechanisms of aging. During the next five years, we will continue to evaluate trajectories of the current biomarkers, while adding novel measures of inflammatory signaling, and inflammation and cellular aging transcriptomic profiles (?inflammaging?). We will enhance our characterization of physical comorbidity and behaviors, including using mobile assessment of physical activity and everyday functioning, and increase the frequency of biomarker assessments to every 18 months. This project is related to the NIMH Strategic Objective # 2: charting mental illness trajectories to determine when, where, and how to intervene. Demonstrating the presence and characterizing the patterns of accelerated biological aging in SZ will significantly advance understanding of the real-world consequences, risk factors, and underlying mechanisms, which together will inform new ways of predicting, tracking, and treating the serious medical co-morbidities and reducing mortality in SZ. The ultimate goal is to improve the overall health and increase the life-span of people living with SZ.